Context-Dependent Roles of Hes1 in the Adult Pancreas and Pancreatic Tumor Formation
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved..
BACKGROUND & AIMS: The Notch signaling pathway is an important pathway in the adult pancreas and in pancreatic ductal adenocarcinoma (PDAC), with hairy and enhancer of split-1 (HES1) as the core molecule in this pathway. However, the roles of HES1 in the adult pancreas and PDAC formation remain controversial.
METHODS: We used genetically engineered dual-recombinase mouse models for inducing Hes1 deletion under various conditions.
RESULTS: The loss of Hes1 expression in the adult pancreas did not induce phenotypic alterations. However, regeneration was impaired after caerulein-induced acute pancreatitis. In a pancreatic intraepithelial neoplasia (PanIN) mouse model, PanINs rarely formed when Hes1 deletion preceded PanIN formation, whereas more PanINs were formed when Hes1 deletion succeeded PanIN formation. In a PDAC mouse model, PDAC formation was also enhanced by Hes1 deletion after PanIN/PDAC development; therefore, Hes1 promotes PanIN initiation but inhibits PanIN/PDAC progression. RNA sequencing and chromatin immunoprecipitation-quantitative polymerase chain reaction revealed that Hes1 deletion enhanced epithelial-to-mesenchymal transition via Muc5ac up-regulation in PDAC progression. The results indicated that HES1 is not required for maintaining the adult pancreas under normal conditions, but is important for regeneration during recovery from pancreatitis; moreover, Hes1 plays different roles, depending on the tumor condition.
CONCLUSIONS: Our findings highlight the context-dependent roles of HES1 in the adult pancreas and pancreatic cancer.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:163 |
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| Enthalten in: |
Gastroenterology - 163(2022), 6 vom: 09. Dez., Seite 1613-1629.e12 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Marui, Saiko [VerfasserIn] |
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| Links: |
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| Themen: |
Hes1 protein, mouse |
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| Anmerkungen: |
Date Completed 22.11.2022 Date Revised 13.12.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1053/j.gastro.2022.08.048 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a BACKGROUND & AIMS: The Notch signaling pathway is an important pathway in the adult pancreas and in pancreatic ductal adenocarcinoma (PDAC), with hairy and enhancer of split-1 (HES1) as the core molecule in this pathway. However, the roles of HES1 in the adult pancreas and PDAC formation remain controversial | ||
| 520 | |a METHODS: We used genetically engineered dual-recombinase mouse models for inducing Hes1 deletion under various conditions | ||
| 520 | |a RESULTS: The loss of Hes1 expression in the adult pancreas did not induce phenotypic alterations. However, regeneration was impaired after caerulein-induced acute pancreatitis. In a pancreatic intraepithelial neoplasia (PanIN) mouse model, PanINs rarely formed when Hes1 deletion preceded PanIN formation, whereas more PanINs were formed when Hes1 deletion succeeded PanIN formation. In a PDAC mouse model, PDAC formation was also enhanced by Hes1 deletion after PanIN/PDAC development; therefore, Hes1 promotes PanIN initiation but inhibits PanIN/PDAC progression. RNA sequencing and chromatin immunoprecipitation-quantitative polymerase chain reaction revealed that Hes1 deletion enhanced epithelial-to-mesenchymal transition via Muc5ac up-regulation in PDAC progression. The results indicated that HES1 is not required for maintaining the adult pancreas under normal conditions, but is important for regeneration during recovery from pancreatitis; moreover, Hes1 plays different roles, depending on the tumor condition | ||
| 520 | |a CONCLUSIONS: Our findings highlight the context-dependent roles of HES1 in the adult pancreas and pancreatic cancer | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Muc5ac | |
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| 650 | 4 | |a Pancreatic Ductal Adenocarcinoma | |
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| 700 | 1 | |a Yokode, Masataka |e verfasserin |4 aut | |
| 700 | 1 | |a Matsumoto, Shimpei |e verfasserin |4 aut | |
| 700 | 1 | |a Muramoto, Yuya |e verfasserin |4 aut | |
| 700 | 1 | |a Ota, Sakiko |e verfasserin |4 aut | |
| 700 | 1 | |a Nakamura, Takeharu |e verfasserin |4 aut | |
| 700 | 1 | |a Yoshida, Hiroyuki |e verfasserin |4 aut | |
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| 700 | 1 | |a Kuriyama, Katsutoshi |e verfasserin |4 aut | |
| 700 | 1 | |a Fukuda, Akihisa |e verfasserin |4 aut | |
| 700 | 1 | |a Saur, Dieter |e verfasserin |4 aut | |
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